Prompt reperfusion of ischemic tissue is critical for restoring normal function. However, this return of blood flow can paradoxically produce a progressive destruction of reversibly damaged cells, thereby leading to tissue dysfunction and infarction. This “reperfusion injury” has multifactorial causes of disease but appears to be strongly associated with an inflammatory response; with the return of blood flow, several inflammatory processes may occur to potentiate ischemic injury, including leukocyte adhesion and infiltration and the release of reactive oxidative species (ROS) such as oxygen free radical species and peroxides, for example H2O2.
Much of this inflammatory response appears to be mediated by interleukins (ILs), a multifunctional subclass of cytokines. Leukocytes (white blood cells) also appear to play a critical role in reperfusion injury. In addition to injuring endothelium and neurons, leukocytes can obstruct the microcirculation directly. This leukocyte capillary plugging also may be the major mechanism of the “no-reflow phenomenon.” Thus areas of parenchyma that are still viable when blood flow returns are not reperfused adequately and ultimately die. Myocardial ischaemia in particular causes extensive capillary plugging.
Ischaemia, and particularly reperfusion, tend to promote an increased release of ROS's from leukocytes which leads to further tissue damage. One of the most damaging types of free radicals is superoxide anions which act to impair endothelial function and the activity of nitric oxide (NO). This further worsens the capillary plugging process because NO has been shown to inhibit platelet aggregation and to prevent leukocyte adherence to the endothelium.
The degree of tissue recovery achieved after ischaemia and reperfusion depends on the nature of the tissue and the severity of the damage.
Ischaemia can be caused by a variety of conditions. For example, acute incidents such as stroke, myocardial infarction or mechanical trauma, and chronic conditions such as atherosclerosis, peripheral vascular disease and diabetes can cause ischaemia. Hypertension is another type of disorder that can lead to ischaemia.
Following an acute incident such as a heart attack caused by a blocked coronary artery, various drugs are delivered intravenously to the heart attack victim to assist in removing any blood vessel obstruction thus re-establishing blood flow leading to reperfusion of tissues. However, this type of treatment is not directed to preventing or ameliorating the tissue damage associated with reperfusion. Creating an environment for reperfusion to occur and re-establish the supply of oxygen to tissue can lead to increased tissue damage by increasing free radical production.
In this respect the conventional treatments for subjects exhibiting ischaemia or at risk of ischaemia are inadequate.
It has been suggested that various substances improve vascular health and function, and that in populations with a diet high in fruits and vegetables there is a lower incidence of coronary arterial disease. This effect has been linked to the beneficial effects of flavonoids, which are polyphenolic compounds that are found in both fruits and vegetables.
Flavonoids are a very large and widespread group of plant derived compounds which are thought to exhibit a number of biological effects including reducing plasma levels of low density lipoproteins, inhibiting platelet aggregation, scavenging free radicals and reducing cell proliferation as well as modulating vascular tone.
A vast number of flavonoids have been identified and differ from one another in the orientation of the hydroxylation or methylation, the position of the benzenoid substituent, the degree of unsaturation and the types of substituents attached. The general three ring structure (A, B and C rings) of many flavonoids are based on the structure of 2-phenyl-4H-1-benzopyran-4-one.

For example, the synthetic flavonoid, 3,4′-dihydroxy flavonol (DiOHF) has a hydroxyl group at the 3,3′- and 4′ positions and has been demonstrated to reduce Infarct and injury associated with myocardial ischaemia and reperfusion during in vitro studies (Shen Wang, Gregory Dusting, Clive May and Owen Woodman, British Journal of Pharmacology (2004) 142, 443-452).
However, the pharmacokinetics of many flavonoids has severely limited their therapeutic usefulness. Synthetic flavonoids tend to be highly lipid soluble molecules and therefore tend to have poor water solubility leading to a difficulty in administration as a therapeutic agent. These characteristics limit their applicability to therapies where acute parenteral administration is desirable, for example in vasodilation therapies.
Given the above identified problems, there remains a need for the development of synthetic flavonoid derivatives with improved aqueous solubility and pharmacokinetics when compared to known flavonoids.